Beyond its potential impact on muscle growth, activin receptors may also contribute significantly to the development of gametocytes, particularly sperm. Additionally, the inactivation or dysfunction of this receptor has been observed in various forms of colorectal cancer and in cases of prostate cancer. ACE-031 is also postulated to influence bone metabolism, adipose tissue accumulation, and sperm health.
What is the mechanism by which ACE-031 exerts its action?
Studies suggest that the mechanism of ACE-031 may involve targeting multiple negative regulators of skeletal muscle growth. While myostatin is considered to be a negative regulator, other members of the transforming growth factor-β (TGF-β) superfamily, such as activin A, bone morphogenetic protein-2 (BMP-2), and BMP-7, may also play roles in inhibiting muscle development and protein synthesis.
Studies have suggested that introducing a soluble form of the activin type IIB receptor (ActRIIB), which is the receptor targeted by ACE-031, may possibly increase muscle mass more effectively than a myostatin-specific neutralizing antibody. Furthermore, in mice lacking myostatin, additional increases in muscle mass may occur when soluble ActRIIB was presented.
Based on this, it is proposed that by targeting multiple negative regulators of skeletal muscle, such as myostatin, activin A, and potentially other TGF-β family members, ACE-031 or similar agents may have a more significant impact on stimulating muscle growth in test models affected by muscle loss and degenerative conditions.(1)
Research Studies on ACE-031 Peptide
ACE-031 Peptide and Energy Metabolism
Studies conducted in mice have provided data to suggest that myostatin may play a role in muscle energy metabolism, specifically highlighting its potential negative impact. Study results suggest that elevated myostatin levels may be associated with excessive muscle fatigue. In experimental settings where the natural form of ACE-031, a myostatin inhibitor, was blocked, a notable increase in serum lactate levels and severe metabolic damage to muscles were reported. Additionally, this inhibition of myostatin may have reduced the number of blood vessels supplying the muscle tissue.
Supplementation with ACE-031, on the other hand, was reported by the research team to promote muscle growth, possibly by inhibiting myostatin and enhancing the oxidative capacity of muscles. This improvement in oxidative capacity may serve as a protective measure against fatigue and the detrimental consequences of free radical production. These findings indicate that ACE-031 supplementation holds potential to enhance muscle function and resilience by modulating myostatin activity and improving muscle energy metabolism.(2)
As per the study reports, “ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.”(2)
ACE-031 Peptide and Muscle Strength
Studies conducted in mice have suggested that ACE-031 influence appears to enhance the force-generating capacity of muscle tissue. This improvement is attributed to the potential preservation of energy supply and a shift in muscle thermodynamics towards oxidative respiration. Notably, the introduction of ACE-031 in mice was reported to yield a significant enhancement in both maximum and total contractile force, exhibiting respective increases of 40% and 25%. Interestingly, there seems to be no discernible impact on overall muscle fatigue, suggesting that ACE-031 may selectively enhance muscle strength without affecting energy dynamics.
Further investigation suggested that ACE-031 may not induce any significant alterations in ATP homeostasis or contractile efficiency, indicating that the observed improvements in force-generating capacity may not be attributable to changes in these parameters. These findings highlight the potential action of ACE-031 in enhancing muscle strength by selectively targeting mechanisms involved in force production, while possibly maintaining energy dynamics and contractile efficiency.(3)
ACE-031 Peptide and Muscle Protection
ACE-031 underwent evaluation in a small-scale clinical trial aimed at assessing its potential to preserve muscle mass among postmenopausal test subjects.(4) In this placebo-controlled trial, results suggest that ACE-031 may have induced increases in lean body mass and thigh muscle volume following a single introduction to the peptide. These effects were reportedly observed after a period of 29 days following the peptide delivery. Significantly, the trial, as per the study reports, yielded an unexpected secondary outcome that merited attention. Test subjects receiving ACE-031 appeared to to have demonstrated improvement in serum biomarkers associated with both bone and fat metabolism. Researchers noted that this observation suggests that while ACE-031’s primary association lies with muscle growth, it likely exhibits inhibitory action on fat storage while simultaneously promoting bone production. As per the researchers, “[ACE-031]… was generally well-tolerated and resulted in increases in muscle mass in healthy postmenopausal [test subjects].”(4)
ACE-031 Peptide and Muscle Growth
Experimental studies in mice have produced data suggesting that myostatin inhibitor such as ACE-031 may induce maximal skeletal muscle growth. Although these findings are in their early stages and require further investigation, they imply that comprehensive muscle protection in conditions characterized by muscle wasting may require a multifaceted approach. This approach may combine interventions that enhance muscle growth, such as growth hormone and IGF-1, with strategies that mitigate muscle wasting, such as ACE-031.(5)
ACE-031 Peptide and Muscle Wasting
Irregular muscle wasting such as in the case of Duchenne Muscular Dystrophy (DMD) or its homologues, is considered to be a genetic disorder inherited in an X-linked recessive manner, and is characterized by profound muscle loss. Subjects with DMD typically experience an inability to mobilize, as their muscles exhibit reduced protein content and unusually high fat content. The underlying cause of DMD is attributed to dysfunctional dystrophin protein, which is considered to render muscle cells weak and susceptible to damage. In addition to this primary action, a secondary consequence appears to arise when myostatin, released from damaged muscle cells, hampers growth in neighboring cells.
Researchers have examined the potential of ACE-031 to possibly mitigate muscle damage by attenuating the secondary impact of myostatin. A recent clinical trial(6) involving ACE-031 appeared to result in a trend towards maintaining muscle function, as evidenced by the preservation of performance on the 6-minute mobility test conducted on the test subjects. Furthermore, results indicated increased lean body mass, improved bone mineral density, and reduced fat mass, which may be attributed to ACE-031 presence. These latter findings align with previous studies suggesting that ACE-031 may exert positive action on bone and fat metabolism. As per researchers, Campbell et. al., myostatin inhibition “is a promising therapeutic approach for DMD”, which may be achieved by controlling the impact of myostatin.
ACE-031 Peptide and Bone Density
In a preclinical study(7) utilizing a mouse model of Duchenne Muscular Dystrophy (DMD), ACE-031 was presented once per week for seven weeks. The mice given ACE-031 appeared to exhibit a significant increase in total body and muscle weight, along with improved bone mineral density. This enhancement in bone mineral density was reportedly attributed to a decrease in osteoclasts, which are responsible for bone breakdown. Additionally, strength testing indicated that the improved mineralization may have resulted in enhanced biomechanics of the bones, potentially leading to increased maximum force tolerance and stiffness. Although the primary focus of this research was to investigate the impact of ACE-031 on muscle cells, the researchers astutely investigated the observed effects on bone. These findings led researchers to posit further the peptide’s potential capacity to enhance muscle strength, increase bone density, and reduce fat deposition.
Another mouse trial(8) also suggested that ACE-031 may exert unique action on bone in addition to its muscle-related potential. In this study, mice were presented with either ACE-031 or a strict myostatin inhibitor, along with a placebo group. While results suggest that both ACE-031 and the myostatin inhibitor may have increased muscle mass, only ACE-031 appeared to improve bone density. This reported increase in bone density seemed to be substantial, with a reported 132% increase observed in the femur and a reported 27% increase in vertebrae density. These findings strongly suggest that ACE-031 may interact with additional molecular targets beyond myostatin, potentially contributing to its distinct action on bone metabolism, as reported in this study.
ACE-031 Peptide and Cancer
In cell culture models, ACE-031 influence was reported by researchers to possibly inhibit the activation of the ERK1/2 pathway in muscle cells. This mechanism may possibly prevent muscle fiber atrophy by impeding programmed cell death. Additionally, studies suggest the potential of the peptide to preserve mitochondrial function and potentially enhance muscle fiber energy efficiency. These actions appear to be particularly relevant in the context of cancer, as ACE-031 may counteract the negative metabolic consequences by potentially improving energy utilization even under conditions of limited nutrition. By optimizing energy usage, ACE-031 might reduce the generation of free radicals during metabolism.9
These cell culture studies have suggested that ACE-031 may prevent muscle cell wasting mediated by myostatin. Cancer cells are considered to directly impact muscle function, including the inactivation of the endogenous form of ACE-031 and the reduction of mitochondrial content in muscle cells, probably leading to diminished energy production.
The potential of ACE-031 in cancer research may extend beyond muscle composition, strength, and lean body mass, as reducing muscle loss in the context of cancer might significantly prolong lifespan. Furthermore, myostatin inhibition in the cancer setting could potentially improve insulin sensitivity, reduce fat accumulation (lipodystrophy), mitigate inflammation, and possibly enhance both bone strength and fracture healing rates.
Researchers consider ACE-031 peptide to be a soluble form of the activin type IIB receptor, which may present a multifaceted approach to potentially enhance muscle growth, preserve muscle function, improve bone health, and mitigate muscle wasting in various conditions, making it a compelling molecule for further scientific investigation and research.
NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.
- Cadena SM, Tomkinson KN, Monnell TE, Spaits MS, Kumar R, Underwood KW, Pearsall RS, Lachey JL. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. J Appl Physiol (1985). 2010 Sep;109(3):635-42. doi: 10.1152/japplphysiol.00866.2009. Epub 2010 May 13. PMID: 20466801; PMCID: PMC2944638. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944638/
- Relizani K, Mouisel E, Giannesini B, Hourdé C, Patel K, Morales Gonzalez S, Jülich K, Vignaud A, Piétri-Rouxel F, Fortin D, Garcia L, Blot S, Ritvos O, Bendahan D, Ferry A, Ventura-Clapier R, Schuelke M, Amthor H. Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy. Mol Ther. 2014 Aug;22(8):1423-1433. doi: 10.1038/mt.2014.90. Epub 2014 May 27. PMID: 24861054; PMCID: PMC4435590. https://pubmed.ncbi.nlm.nih.gov/24861054/
- Béchir N, Pecchi E, Vilmen C, Le Fur Y, Amthor H, Bernard M, Bendahan D, Giannesini B. ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo. FASEB J. 2016 Oct;30(10):3551-3562. doi: 10.1096/fj.201600271RR. Epub 2016 Jul 14. PMID: 27416839. https://pubmed.ncbi.nlm.nih.gov/27416839/
- Attie KM, Borgstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE, Kumar R, Willins DA, Seehra JS, Sherman ML. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013 Mar;47(3):416-23. doi: 10.1002/mus.23539. Epub 2012 Nov 21. PMID: 23169607. https://pubmed.ncbi.nlm.nih.gov/23169607/
- Morvan F, Rondeau JM, Zou C, Minetti G, Scheufler C, Scharenberg M, Jacobi C, Brebbia P, Ritter V, Toussaint G, Koelbing C, Leber X, Schilb A, Witte F, Lehmann S, Koch E, Geisse S, Glass DJ, Lach-Trifilieff E. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12448-12453. doi: 10.1073/pnas.1707925114. Epub 2017 Nov 6. PMID: 29109273; PMCID: PMC5703284. https://pubmed.ncbi.nlm.nih.gov/29109273/
- Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, Wilson DM, Sherman ML, Escolar D, Attie KM. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve. 2017 Apr;55(4):458-464. doi: 10.1002/mus.25268. Epub 2016 Dec 23. PMID: 27462804. https://pubmed.ncbi.nlm.nih.gov/27462804/
- Puolakkainen T, Ma H, Kainulainen H, Pasternack A, Rantalainen T, Ritvos O, Heikinheimo K, Hulmi JJ, Kiviranta R. Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy. BMC Musculoskelet Disord. 2017 Jan 19;18(1):20. doi: 10.1186/s12891-016-1366-3. PMID: 28103859; PMCID: PMC5244551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244551/
- Bialek P, Parkington J, Li X, Gavin D, Wallace C, Zhang J, Root A, Yan G, Warner L, Seeherman HJ, Yaworsky PJ. A myostatin and activin decoy receptor enhances bone formation in mice. Bone. 2014 Mar;60:162-71. doi: 10.1016/j.bone.2013.12.002. Epub 2013 Dec 9. PMID: 24333131. https://pubmed.ncbi.nlm.nih.gov/24333131/
- Lokireddy S, Wijesoma IW, Bonala S, Wei M, Sze SK, McFarlane C, Kambadur R, Sharma M. 1) Myostatin is a novel tumoral factor that induces cancer cachexia. Biochem J. 2015 Feb 15;466(1):201. doi: 10.1042/bj4660201u. Erratum for: Biochem J. 2012 Aug 15;446(1):23-36. PMID: 25656055; PMCID: PMC8086604. https://pubmed.ncbi.nlm.nih.gov/25656055/
- Image Source: National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 118732224, Myostatin inhibitory peptide 7. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Myostatin-inhibitory-peptide-7.
Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.